Antituberculous drugs: An overview

INTRODUCTION — Pharmacologic agents for treatment of tuberculosis (TB) are utilized in a hierarchical fashion [1-5].

First-line agents for treatment of TB disease consist of isoniazid, a rifamycin (rifampin or [less frequently] either rifapentine or rifabutin), pyrazinamide, and ethambutol; in addition, moxifloxacin is a first-line agent when administered in combination with isoniazid, rifapentine, and pyrazinamide [6]. Dosing for first-line agents for treatment of TB disease in adults is summarized in the tables (table 1 and table 2) [1].

Presence of drug resistance, contraindication, or intolerance to first-line agents may warrant substitution with one or more second-line agents. Categories of second-line agents are summarized in the table (table 3). Dosing for second-line agents is summarized in the table (table 4). Further details regarding treatment of multidrug-resistant TB are provided in guidelines published by the American Thoracic Society [2] and the World Health Organization [4].

Pharmacologic issues and some clinical data related to use of antituberculous drugs are reviewed here; issues related to clinical use of antituberculous drugs in therapeutic regimens are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults" and "Tuberculosis disease in children: Treatment and prevention".)

TERMINOLOGY — TB terminology is inconsistent in the literature [7]. Relevant terms are defined in the table (table 5).

FIRST-LINE AGENTS — First-line antituberculous agents for treatment of susceptible TB consist of isoniazid, a rifamycin (usually rifampin), ethambutol, pyrazinamide, and moxifloxacin (when administered in combination with isoniazid, rifapentine, and pyrazinamide). The clinical approach to use of these agents is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Tuberculosis disease in children: Treatment and prevention".)

Dosing for first-line agents is summarized in the tables (table 1 and table 2).

Issues related to isoniazid are discussed further separately. (See "Isoniazid: An overview" and "Isoniazid hepatotoxicity" and "Isoniazid (INH) poisoning".)

Issues related to rifampin and the other rifamycins are discussed further separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

Issues related to ethambutol are discussed further separately. (See "Ethambutol: An overview".)

Issues related to pyrazinamide are discussed further separately. (See "Pyrazinamide: An overview".)

Issues related to use of moxifloxacin in a shortened four-month regimen are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Rifapentine-moxifloxacin-based four-month regimen'.)

SECOND-LINE AGENTS — Evidence of drug resistance, contraindications, or intolerance to first-line antituberculous agents warrants use of second-line agents. These agents are so classified because of decreased activity against Mycobacterium tuberculosis, relative lack of clinical data, unfavorable or poorly characterized pharmacokinetic profile, and/or increased incidence and severity of adverse events compared with first-line agents [1,8].

Selection of second-line antituberculous agents should be guided by in vitro susceptibility results with involvement of an expert in the treatment of TB. In the setting of severe illness, treatment with second-line agents may need to be initiated prior to availability of drug susceptibility results. In such cases, treatment decisions should be based on the drug susceptibility pattern of the source case to whom the patient has been exposed, prior treatment regimens of the patient (ie, agents that have not been used previously are preferred), and the likelihood of cross-resistance based on previous agents used (table 3). Dosing and adverse effects for second-line agents are summarized in the table (table 4). The clinical approach to use of second-line agents is discussed further separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

Oral agents

Bedaquiline — Bedaquiline is an oral diarylquinoline drug with bactericidal antituberculous activity approved by the US Food and Drug Administration (FDA) in 2012 for treatment of multidrug-resistant (MDR)-TB. Guidelines regarding its use were published by the United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) [3,9].

Bedaquiline has become an important option for the treatment of drug-resistant pulmonary TB. It may be used as part of combination therapy for treatment of pulmonary, MDR-TB via directly observed therapy as part of combination therapy when an effective treatment regimen cannot otherwise be provided [3]. The approach to use of bedaquiline for treatment of drug-resistant TB is discussed in detail separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults" and "Tuberculosis disease in children: Treatment and prevention".)

The CDC issued 2013 guidelines for bedaquiline use in populations not included in the clinical trials for the drug (and hence not covered by the FDA approval), including children, pregnant women, individuals with extrapulmonary MDR-TB, and individuals with HIV or other comorbid conditions [9]. The CDC indicated that bedaquiline may be used on a case-by-case basis for these individuals when an effective treatment regimen cannot otherwise be provided. The WHO 2020 guidelines concluded no major safety concerns for bedaquiline (>6 months’ duration), the use of bedaquiline with delamanid, or bedaquiline use during pregnancy [3].

Bedaquiline can cause QT prolongation, leading to cardiac arrhythmia and/or death. In data submitted to the FDA, death was observed more frequently among patients receiving bedaquiline than among those treated with other antituberculous agents (11.4 versus 2.5 percent) [10]. However, in subsequent larger clinical studies, bedaquiline appeared to be safer than in the initial trials [11,12].

Patients on bedaquiline should be monitored for symptoms of cardiac toxicity and by electrocardiogram (ECG) [13]. An ECG should be obtained at baseline and repeated at least 2, 12, and 24 weeks after starting treatment, as well as in the setting of syncope. Weekly ECGs are warranted for patients with increased risk of QT prolongation (this includes patients with history of torsade de pointes, congenital long QT syndrome, hypothyroidism, bradyarrhythmia, uncompensated heart failure, as well as patients on other QTc-prolonging drugs (table 6)). Discontinuation of bedaquiline is warranted in the setting of clinically significant ventricular arrhythmia or QTc F >500 ms. Serum potassium, calcium, and magnesium should be obtained at baseline and monitored until fully corrected.

Bedaquiline is a cytochrome P450 substrate; therefore, coadministration with strong CYP3A4 inducers (such as rifampin, rifapentine, and rifabutin) or inhibitors should be avoided whenever possible.

Bedaquiline has a terminal serum half-life of four to five months [14,15]. To minimize the likelihood of bedaquiline resistance, it may be discontinued prior to other active drugs; at least three other agents should be included for the remainder of treatment [3].

Cross-resistance between bedaquiline and clofazimine has been observed via mutation in the Rv0678 regulatory gene, resulting in upregulation of an efflux pump [16-18].

Clofazimine — Clofazimine is a semisynthetic riminophenazine postulated to disrupt electron transport and generate reactive oxygen species [19]. In general, the availability of clofazimine is limited to regions where it is used for the treatment of leprosy [20]. In the United States, use of clofazimine for treatment of drug-resistant TB requires submission of an investigational new drug application to the FDA.

Adverse effects of clofazimine include photosensitivity, brownish skin discoloration, ichthyosis, QT prolongation, neurologic, and gastrointestinal (GI) intolerance [21]. Caution is warranted when administering clofazimine with other agents that may also cause QT prolongation (table 6).

Cross-resistance between bedaquiline and clofazimine has been observed via mutation in the Rv0678 regulatory gene, resulting in upregulation of an efflux pump [16,17]. Therefore, in patients who have failed a regimen with one of these drugs, it may be prudent to avoid use of the other.

Cycloserine — Cycloserine disrupts peptidoglycan synthesis as a competitive inhibitor of alanine racemase and D-alanine:D-alanine ligase [22]. It should be administered via dose escalation over a two-week period as summarized in the table (table 4). A study observed that such dosing for cycloserine (250 to 500 mg once or twice daily) would likely be inadequate for isolates with MICs >16 mcg/mL [23]. Divided dosing had no negative impact on attaining target exposure but could potentially reduce cycloserine-induced adverse effects. Serum drug concentrations should be monitored for all patients on cycloserine [5]. (See 'Serum drug concentration monitoring' below.)

Cycloserine may be associated with neuropsychiatric adverse reactions; therefore, it should be used with caution in patients with pre-existing mental health issues. When possible, cycloserine should also be avoided in patients with a history of seizure disorder. Peripheral neuropathy is common in patients taking cycloserine and is more commonly observed in patients with impaired drug clearance [24]. Pyridoxine 25 to 50 mg/day may be coadministered in attempts to prevent neuropathy; however, data are lacking regarding efficacy. Higher doses of pyridoxine (150 to 200 mg/day) in patients receiving cycloserine have been associated with an increased risk of neuropathy [24]. (See 'Central nervous system toxicity' below.)

Delamanid — Delamanid is an oral nitro-dihydro-imidazo-oxazole drug that inhibits mycolic acid synthesis [25,26]. It has been conditionally approved for use in the treatment of MDR-TB by the European Medicines Agency but has not yet received FDA approval for use in the United States [27].

Delamanid may be used in TB treatment regimens among adults with pulmonary MDR-TB when an effective and well-tolerated regimen cannot be composed with conventional second-line drugs. Patients for whom delamanid may be particularly useful include those with increased risk for poor outcomes (such as drug intolerance or contraindication, extensive or advanced disease, resistance to fluoroquinolones and/or aminoglycosides/capreomycin, and extensively drug-resistant [XDR] TB) [26,28].

Delamanid is a substrate of CYP3A4; therefore, caution should be exercised in patients receiving CYP3A4 inducers (such as rifampin) and inhibitors (such as ritonavir).

Delamanid can cause QT prolongation, leading to cardiac arrhythmia and/or death; caution is warranted when administering delamanid with other agents that may cause QT prolongation (table 6). In one study, combining delamanid with bedaquiline was associated with only modest (no more than additive) QTc prolongation [29]. The WHO 2020 guidelines concluded no major safety concerns for use of bedaquiline with delamanid [3].

Ethionamide — Ethionamide may be used for treatment of drug-resistant TB if the isolate is known to be susceptible to ethionamide via conventional in vitro testing or if molecular testing demonstrates no evidence of mutations in the inhA gene, since mutations in this gene can confer resistance to ethionamide (in addition to isoniazid resistance) [5]. In the setting of known isoniazid resistance and in the absence of confirmed ethionamide susceptibility, use of ethionamide should be deferred.

Ethionamide should be administered via dose escalation over a two-week period as summarized in the table (table 4). However, it is uncertain whether such dosing obtains the targeted drug exposures needed for efficacy [30,31].

The combination of ethionamide and para-aminosalicylic acid is likely to cause hypothyroidism as well as GI side effects. Patients may tolerate one of these two drugs but may not tolerate both together. (See 'Adverse effects' below.)

Fluoroquinolones: levofloxacin or moxifloxacin — Fluoroquinolones have excellent activity in vitro against M. tuberculosis and represent the initial category of second-line antituberculous agents in the setting of resistance and/or intolerance to first-line agents [32,33]. In addition, moxifloxacin is a first-line agent when administered in combination with isoniazid, rifapentine, and pyrazinamide [6]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Rifapentine-moxifloxacin-based four-month regimen'.)

In general, levofloxacin and moxifloxacin are favored over the early-generation fluoroquinolones (specifically ciprofloxacin) for treatment of TB, due to greater in vitro activity [34-42]. In one study including 834 patients with suspected drug-resistant TB, mortality rates among those treated with either moxifloxacin or levofloxacin were half those of participants not treated with any fluoroquinolone or treated only with an earlier-generation fluoroquinolone (adjusted hazard ratio 0.46, 95% CI 0.26-0.80) [41]. Since all fluoroquinolones share a genetic target (deoxyribonucleic acid [DNA] gyrase), there is no role for simultaneous use of more than one drug in this class [43-45].

Cross-resistance between fluoroquinolones is common but not universal [5,46]. When fluoroquinolone resistance is detected by culture-based drug susceptibility testing or molecular testing, an MIC for moxifloxacin may be performed to determine whether an increased dose may be considered. Use of "high-dose" moxifloxacin (600 mg or 800 mg orally once daily) may achieve adequate serum concentrations in patients for whom the isolate's MIC to moxifloxacin is 1 to 2 mcg/mL. However, this approach has not been studied in clinical trials, and the safety of such dose escalations has not been established [5].

The fluoroquinolones are generally well-tolerated. Rare complications include tenosynovitis (including reports of Achilles tendinitis and rupture) and exacerbation of symptoms among patients with myasthenia gravis and peripheral neuropathy [47,48]. Levofloxacin is less frequently associated with QT interval prolongation than moxifloxacin (standard dose), so levofloxacin may be preferred for patients on a regimen including other agents associated with QT prolongation (including clofazimine, bedaquiline, and delamanid) (table 4). Moxifloxacin does not require dose adjustment in patients with renal insufficiency (unlike levofloxacin).

Data supporting use of higher doses of levofloxacin (1000 mg/day) come from a small randomized trial and a pharmacokinetic study [49-51]. In a previous trial including 182 patients with MDR-TB randomized to receive either levofloxacin (750 mg/day) or moxifloxacin (with a background drug regimen), both drugs were associated with high rates of culture conversion at three months [35]. Prior to these studies, data on levofloxacin administered at a lower dose (500 mg/day) suggested that levofloxacin was less effective than moxifloxacin or gatifloxacin [43].

Additional issues related to fluoroquinolones are discussed further separately. (See "Fluoroquinolones".)

Linezolid — Linezolid may be used for treatment of MDR- and XDR-TB or in settings of intolerance to other drugs [52]. It should be used with caution and close monitoring as its use is often limited by adverse effects such as bone marrow suppression, neuropathy, GI symptoms, and/or retinitis [53-59]. (See 'Adverse effects' below.)

Development of linezolid toxicity should prompt dose reduction (eg, from 600 to 300 mg orally once daily). In such cases, a serum drug concentration should be measured to ensure the concentration is within the therapeutic range. In addition, studies have suggested that such dose reductions will not likely obtain the target drug exposure needed for efficacy [60,61].

Linezolid should not be administered concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or a diet high in tyramine-containing foods (such as cheese, red wine, cured meats, soy sauce, and fermented foods), given the risk of serotonin syndrome. If linezolid therapy is planned and when possible, SSRIs and TCAs should be withdrawn at least two weeks in advance (given the long half-lives of these agents).

In one report including 41 patients with XDR-TB in South Korea, sputum cultures converted to negative after addition of linezolid in 87 percent of cases [58]. Significant cumulative toxicity was observed, including peripheral neuropathy at low and high doses of linezolid (60 percent at 300 mg/day and 80 percent at 600 mg/day). These rates are significantly higher than those observed in patients receiving linezolid for other indications.

Linezolid has been evaluated in combination with bedaquiline and pretomanid for treatment of highly resistant TB. In general, this regimen should be considered in MDR-TB patients with resistance to fluoroquinolones and no previous exposure to bedaquiline and linezolid for >2 weeks [3]. (See "Treatment of drug-resistant pulmonary tuberculosis in adults", section on 'Bedaquiline, pretomanid, linezolid'.)

Para-aminosalicylic acid — Para-aminosalicylic acid (not available in the United States or Canada) is bacteriostatic; it has limited efficacy for treatment of TB and is poorly tolerated (due to GI and endocrine side effects [including hypothyroidism], particularly when administered in combination with ethionamide) [5]. (See 'Adverse effects' below.)

Para-aminosalicylic acid should be administered via dose escalation over a two-week period as summarized in the table (table 4).

The combination of para-aminosalicylic acid and ethionamide is likely to cause hypothyroidism as well as GI side effects. Patients may tolerate one of these two drugs but may not tolerate both together. (See 'Adverse effects' below.)

Pretomanid — Pretomanid, a nitroimidazole, has bactericidal activity [62-64]. A regimen of pretomanid, bedaquiline, and high-dose linezolid has FDA approval for treatment of patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

Thioacetazone — Thioacetazone has bacteriostatic activity against TB. Toxicity is high, and its use should be restricted to cases with broad resistance. Thioacetazone should not be administered to patients with HIV infection; such patients are at increased risk for drug-induced Stevens-Johnson syndrome [65]. Thioacetazone is not available in the United States, and reliable formulations are unavailable in many areas.

Injectable-only agents

Aminoglycosides and capreomycin — Second-line injectable-only agents for treatment of TB include aminoglycosides (amikacin, streptomycin, kanamycin) and capreomycin (a polypeptide). In general, amikacin is the preferred agent (due to general availability of the drug and serum concentration monitoring). Use of streptomycin is generally restricted to the setting of known in vitro susceptibility (given high rates of drug resistance), no history of prior use, and contraindication to amikacin. Kanamycin and capreomycin are no longer recommended by the WHO for use in MDR-TB regimens [4].

There is no role for use of more than one of these injectable agents in a treatment regimen, given their common mechanism of action (eg, protein synthesis inhibition) [44,45].

Cross-resistance among the injectable-only agents has been observed and may be helpful in predicting use of alternate agents in the setting of prior injectable exposure (pending definitive susceptibility data) [66-71]. Cross-resistance between amikacin and capreomycin is incomplete, while streptomycin-resistant isolates are often susceptible to other aminoglycosides or capreomycin (unless they have been used previously).

Second-line injectable-only agents can be given either intramuscularly or intravenously. For patients who cannot tolerate repeated intramuscular injections, intravenous therapy may be administered. They are typically given five days per week; they should be administered seven days per week for patients who are severely ill. The initial duration of daily therapy (referred to as the "intensive phase" of treatment) is administered until culture conversion is documented (at least two to three months and can be up to six months). After culture conversion, three-days-per-week dosing can be used for the remaining duration (referred to as the "continuation phase" of treatment [normally through at least six months and up to 18 months beyond culture conversion]).

Serum drug concentration monitoring is warranted for all aminoglycosides and capreomycin given their potential for nephrotoxicity and consequent electrolyte disorders [72]. In addition, the aminoglycosides can cause eighth cranial nerve damage. Renal function should be assessed regularly, and audiometry performed on a monthly basis. (See 'Serum drug concentration monitoring' below and "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

Carbapenems plus clavulanate — M. tuberculosis is resistant to beta-lactam antibiotics in vitro, but resistance may be overcome in some isolates by inhibiting the beta-lactamase with clavulanate [73]. The combination of carbapenems (either imipenem-cilastatin or meropenem) with clavulanate (a beta-lactamase inhibitor) has been shown to be bactericidal against M. tuberculosis, and some clinical efficacy has been observed in a small number of patients [74-76]. However, data from controlled clinical trials to evaluate safety and efficacy of such treatment are lacking.

Use of carbapenems is limited by high cost, intravenous administration, and limited clinical experience. Use of ertapenem once daily intramuscularly or intravenous administration may be considered in place of imipenem-cilastatin or meropenem for patients continuing carbapenem therapy in an outpatient setting [2]. Since clavulanate is not available as a single formulation, coadministration of amoxicillin-clavulanate is required to provide 125 mg of the clavulanate for each carbapenem dose.

DIRECTLY OBSERVED THERAPY — All patients with TB should receive directly observed therapy (DOT) when available as part of patient-centered case management [1]. This is most important in those receiving intermittent therapy and in special populations (such as patients with HIV, homeless patients, or patients otherwise at high risk of treatment failure). Ideally, DOT should occur seven days per week. If this is not possible, five-days-per-week DOT may be used for patients who are not hospitalized, with self-administration of medications on weekends during the induction phase or before the patient becomes smear negative. Subsequently, treatment may be five days per week via DOT. (See "Adherence to tuberculosis treatment".)

SERUM DRUG CONCENTRATION MONITORING — Monitoring of serum concentrations for antituberculous therapy is warranted for select patients as summarized below (in settings where serum drug concentrations can be obtained). Data to establish a target range associated with efficacy are lacking for many agents; rather, target concentrations are based on the known pharmacodynamics of the agent, exposures in normal volunteers, as well as serum concentrations observed during clinical trials. While such monitoring does not ensure clinical success, it does provide guidance for dose adjustments to optimize drug efficacy and safety.

Antituberculous serum drug concentration monitoring should be pursued in the following circumstances:

●Drug-resistant tuberculosis

●Lack of clinical response or relapse while on appropriate drugs administered via directly observed therapy

●Known or suspected drug malabsorption (eg, underlying diabetes mellitus with gastroparesis, alcohol use, select gastrointestinal disorders)

●Regimen with potentially significant drug-drug interactions, such as combination of rifamycins and select antiretrovirals (most notably protease inhibitors)

●Moderate to severe renal impairment (including those receiving renal replacement therapy) for agents with significant renal clearance

●HIV coinfection (especially those with low CD4 lymphocyte counts and those receiving antiretrovirals known to interact with antituberculous therapy)

●Use of aminoglycosides, capreomycin, or cycloserine

●Antituberculous regimen with few effective drugs (to optimize the effect of the available drugs)

●Use of antituberculous doses lower than standard therapy because of drug intolerance or higher (due to prior failure to reach adequate drug exposures)

Serum drug concentration monitoring should be performed following initiation of treatment or regimen adjustments, after steady-state concentrations have been achieved. In patients with delayed absorption, serum concentrations obtained two hours after the dose may fail to accurately characterize drug absorption. To address this concern, collecting samples two and six hours after drug administration may be used to evaluate the extent and rate of drug absorption [77].

The target peak concentrations, intervals between drug administration, and serum collection times for therapeutic monitoring of antituberculous drugs are summarized in the table (table 7) [77].

ADVERSE EFFECTS

Clinical and laboratory monitoring — Treatment of patients with tuberculosis requires careful monitoring for adverse drug effects. This is especially important when second-line agents are used and/or when drug doses are escalated.

Patients receiving combination antituberculous therapy should undergo baseline measurement of liver function tests (serum bilirubin, alkaline phosphatase, and transaminases). In addition, testing for hepatitis B and C should be pursued for patients with epidemiologic risk factors [78]. Counseling and testing for HIV infection should also be performed. Other baseline tests prior to initiation of antituberculous therapy should include complete blood count, creatinine, and uric acid [1].

Patients on regimens including drugs associated with hepatotoxicity (notably isoniazid, rifampin, pyrazinamide, moxifloxacin, ethionamide, and para-aminosalicylic acid) should be counseled to avoid use of alcohol and drugs associated with hepatotoxicity (such as acetaminophen). Patients should be educated about the signs and symptoms of hepatic toxicity. These include anorexia, nausea, vomiting, dark urine, icterus, rash, pruritus, fatigue, fever, abdominal discomfort (particularly right upper quadrant discomfort), easy bruising or bleeding, and arthralgias [79]. Patients should be questioned directly at monthly visits for these symptoms and should know to immediately report any signs or symptoms that occur in the interval between the monthly visits. Patients should also be assessed for symptoms of peripheral neuropathy. All symptomatic patients should be evaluated clinically and have liver function tests performed.

Serial liver function measurements are not necessary for patients with normal baseline results and no risk for hepatitis. Monthly liver function tests are warranted in the following settings:

●Abnormal baseline liver function tests

●Suspected drug reaction

●Underlying liver disease (such as viral hepatitis)

●Pregnancy and the first three months postpartum

●Use of pyrazinamide in continuation phase

●Other situations that may be associated with hepatic injury (eg, some medications, alcohol or drug abuse)

Issues related to hepatoxicity associated with antituberculous drugs are discussed below and separately. (See 'Hepatotoxicity' below and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Additional clinical and laboratory monitoring should be tailored to the treatment regimen. Examples include:

●Ethambutol or clofazimine – Monitor visual acuity and red-green color discrimination (monthly). Vision disturbance may occur related to ethambutol-induced optic nerve dysfunction; however, vision changes should also prompt consideration of tuberculous meningitis under the appropriate circumstances. (See "Tuberculous meningitis: Clinical manifestations and diagnosis".)

●Aminoglycosides or capreomycin – Monitor renal function, electrolytes (potassium, calcium, magnesium), and signs of ototoxicity monthly (including audiology testing and evaluation for tinnitus and vestibular toxicity).

●Ethionamide or para-aminosalicylate – Monitor thyroid stimulating hormone (every three months).

●Cycloserine – Monitor for psychiatric symptoms, particularly depression and mood changes (monthly).

●Linezolid – Monitor blood counts (weekly during initial phase, then monthly) and for signs and symptoms of peripheral neuropathy and retinitis.

●Bedaquiline, fluoroquinolones, clofazimine, delamanid – Monitor electrocardiogram (at least 2, 12, and 24 weeks following initiation of treatment, and up to weekly if these agents are used in combination or patient has other risk factors) for QTc prolongation.

Manifestations and their management — Antituberculous drugs are associated with a broad array of adverse effects, as discussed by system in the following sections. Some adverse effects may be managed symptomatically with continuation of the drug, some may be managed with dose adjustment and careful monitoring, and some require drug discontinuation with broad reconsideration of the treatment regimen. Patients should be counseled regarding frequent and/or severe adverse effects and ways to minimize such reactions. Timing of administration (relative to food or bedtime) may help to minimize some adverse effects. Expert consultation should be sought in complex situations.

Gastrointestinal effects — A number of antituberculous agents may be associated with gastrointestinal (GI) symptoms. These include (but are not limited to) ethionamide, para-aminosalicylic acid, linezolid, levofloxacin, moxifloxacin, clofazimine, and bedaquiline.

Patients with GI complaints should be evaluated clinically and a differential diagnosis should be considered based on signs and symptoms. Strategies for management of GI symptoms attributed to antituberculous drugs include judicious symptomatic management (ie, use of antiemetics, antidiarrheals, treatment of reflux [note that antacids cannot be given within two hours of fluoroquinolones]), minimizing other GI irritants (such as nonsteroidal anti-inflammatory agents), spacing medications during the day, administering the causative agent at bedtime, administering medication following a light snack, and encouraging hydration.

It may be possible to make drug dose adjustments, as follows:

●Ethionamide and para-aminosalicylic acid – Ethionamide often causes upper GI symptoms such as nausea and vomiting, while para-aminosalicylic acid causes lower GI symptoms (such as abdominal cramping and diarrhea); however, symptoms may overlap. Patients may not tolerate both together.

If either ethionamide or para-aminosalicylic acid is suspected of causing GI symptoms, both drugs may be held for 3 to 4 days. If the symptoms improve off the medication, they may be restarted (1 drug at a time) at a lower dose (often in 2 or 3 daily administrations), and gradually increased over the next 2 weeks. Ethionamide may be initiated at 250 mg daily and increased to at least 500 mg daily. Para-aminosalicylic acid may be initiated at 2 to 4 grams daily and increased to 6 to 8 grams daily. Patients may tolerate a higher dose of ethionamide in the evening (such as 250 mg in the morning and 500 mg at bedtime). Once the titration is complete, steady-state serum drug concentrations should be monitored to determine whether the concentration is therapeutic.

●Linezolid – If linezolid is suspected of causing GI symptoms, the dose may be reduced from 600 mg to 300 mg orally once daily. In such cases, a serum concentration should be measured to document whether the concentration is therapeutic.

●Clofazimine – If clofazimine is suspected of causing nausea/vomiting, the dose may be reduced to 100 mg orally once daily.

Drug doses for fluoroquinolones should not be reduced. Fluoroquinolones are a critical class in the treatment regimen of drug-resistant tuberculosis (TB), and the bactericidal effects are dose dependent. In addition, antacids containing magnesium, aluminum, or calcium may reduce fluoroquinolone absorption and should be avoided within two to four hours of the fluoroquinolone dose.

Drug doses for bedaquiline should not be adjusted pending further data regarding this agent.

Hepatotoxicity — Gastrointestinal complaints may represent antituberculous hepatotoxicity. Antituberculous drugs associated with hepatotoxicity include isoniazid, rifampin, pyrazinamide, and para-aminosalicylic acid. Antituberculous drugs not commonly associated with hepatotoxicity include ethambutol, aminoglycosides, and cycloserine. Rarely, fluoroquinolones (levofloxacin and moxifloxacin) have been associated with acute liver injury.

Patients on regimens including drugs associated with hepatotoxicity should be counseled to avoid use of alcohol and drugs associated with hepatotoxicity (such as acetaminophen). Risk factors for drug-induced liver injury include underlying liver disease (particularly hepatitis C) and coadministration of antiretroviral therapy for patients with HIV infection.

The approach to management of hepatotoxicity associated with antituberculous drugs should be guided by liver function test results and the agent(s) most suspected of causing such results (algorithm 1 and algorithm 2). In general, all hepatotoxic drugs should be discontinued if the serum bilirubin is ≥3 mg/dL (≥51 mcmol/L) or serum transaminases are more than five times the upper limit of normal.

Once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring between resumption of each agent. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Dermatologic effects — Dermatologic reactions secondary to antituberculous therapy may range from mild local effects (not requiring treatment or modification of therapy) to a manifestation of a severe, life-threatening reaction. Antituberculous drugs should be discontinued in the setting of systemic symptoms, fever, mucous membrane involvement, blistering, edema of the lips or eyes, wheezing, or airway compromise.

Dermatologic reactions associated with antituberculous drugs include (see "Drug eruptions"):

●Maculopapular rash and pruritus – All antituberculous drugs may cause a maculopapular rash and/or pruritus, some of which resolve after several weeks despite treatment continuation. Other sources of such symptoms should be explored. Mild reactions may be managed symptomatically (with antihistamines or topical corticosteroids) with continuation of the drugs.

●Hives (urticaria) – Hives (urticaria) may be caused by any antituberculous drug. With anti-TB drugs, hives can occur with or without fever. The drug that most commonly causes this type of reaction is isoniazid, followed by rifampin, pyrazinamide, ethionamide, cycloserine, ethambutol, para-aminosalicylic acid, and streptomycin. Fluoroquinolones and bedaquiline have also been implicated, but the frequency compared with the other drugs is not reported. In children, this presentation may occur during a coincident viral infection (eg, Epstein-Barr or herpes simplex), and the child should be examined for other signs of viral infection and a complete blood count obtained for possible lymphocytosis. All potentially responsible drugs should be stopped until the reaction resolves, although, if a child is found to have evidence of viral infection, all medications can be resumed.

In all adults and in children without evidence of a viral infection, rechallenge is recommended for the purpose of identifying the drug responsible for the reaction and resuming the other medications. Rechallenge is appropriate only if the reaction was not severe and there was no evidence of anaphylaxis (ie, concomitant angioedema, hoarse voice, throat tightness, sudden-onset cough, wheezing, mental status change, nausea or vomiting, lightheadedness, or hypotension). Rechallenge is also contraindicated if the patient's reaction had features of Stevens-Johnson syndrome, toxic epidermal necrolysis, or systemic hypersensitivity syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS), as detailed below. (See 'Severe systemic reactions' below.)

Rechallenge should be performed with one medication at a time, at approximately four-day intervals. A protocol used in the Philadelphia Tuberculosis Control Program is provided (table 8) [5].

●Flushing – Flushing (in the absence of rash, with or without redness and watering of the eyes) within two to three hours of drug administration is most often associated with rifampin and pyrazinamide. The reaction is usually mild and self-limited; if bothersome, it may be managed with an antihistamine. Flushing with or without hot flashes, palpitations, or headache two to three hours after consuming tyramine-containing foods (such as cheese, red wine, cured meats, soy sauce, and fermented foods) may be observed in patients taking isoniazid. This can generally be managed with avoidance of the precipitating foods.

●Photosensitivity and hyperpigmentation – Patients on pyrazinamide, clofazimine, or fluoroquinolones are at increased risk for photosensitivity, which may persist for prolonged periods even after the causative drug is stopped. Patients receiving these agents should limit sun exposure and use sunscreen. Rifabutin has been associated with pseudojaundice (brownish discoloration of the skin with clear sclera and normal liver enzymes). Clofazimine-induced hyperpigmentation may also worsen with sun exposure but is usually reversible upon drug discontinuation.

●Lichenoid reactions – Several antituberculous drugs (most notably ethambutol, isoniazid, streptomycin, and cycloserine) can cause lichenoid reactions (pruritic, violaceous papules most commonly involve the wrists, shins, and back). Mucous membranes and scalp may also be involved. Lesions may resolve while medication continues, and medication should not be discontinued unless an equally effective drug is available for substitution. (See "Lichenoid drug eruption (drug-induced lichen planus)".)

●Superficial fungal infection – Cutaneous or mucocutaneous candidiasis secondary to fluoroquinolones and linezolid occurs more commonly in diabetics and generally responds to topical antifungal therapy.

●Alopecia – Temporary alopecia has been reported in patients receiving isoniazid or ethionamide.

Antituberculous drugs should be discontinued in the setting of systemic symptoms, fever, mucous membrane involvement, blistering, edema of the lips or eyes, wheezing, or airway compromise.

Severe systemic reactions — Severe systemic reactions associated with antituberculous drugs include:

●Anaphylaxis – Anaphylaxis is rare and presents within minutes of medication dosing as urticaria, angioedema, pruritus, hypotension, and respiratory symptoms. (See "Anaphylaxis: Acute diagnosis".)

Drugs suspected to have caused anaphylaxis should be discontinued. Rechallenge should not be attempted. The patient should be referred to an allergy specialist for possible desensitization utilizing facilities equipped to respond to the potential for life-threatening anaphylaxis. Skin testing for immunoglobulin (Ig)E using the primary drug is almost never useful because the hepatic metabolism of these medications produces neoantigens that are not present in the original drug. Oral desensitization protocols have been published for isoniazid, rifampin, and ethambutol [80,81] and can be devised for almost any drug. Issues related to drug desensitization are discussed further separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

●Drug reaction with eosinophilia and systemic symptoms – DRESS (also known as drug-induced hypersensitivity syndrome [DIHS]) is a rare but potentially life-threatening syndrome secondary to the administration of antituberculous medications (most commonly rifampin, isoniazid, and ethambutol). Signs and symptoms (usually beginning two to eight weeks after drug initiation) can include fever, malaise, lymphadenopathy, rash, facial edema, mucous membrane involvement, and liver function abnormalities. Once a drug has been identified as the causative agent, it should be discontinued. Rechallenge should not be attempted. Issues related to DRESS are discussed further separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Stevens-Johnson syndrome and toxic epidermal necrolysis – These are severe mucocutaneous reactions characterized by drug-induced extensive necrosis and detachment of the epidermis. Once a drug has been identified as the causative agent, it should be discontinued. Rechallenge should not be attempted. These entities are discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

QT prolongation — Drugs associated with QT interval prolongation include bedaquiline, clofazimine, delamanid, and fluoroquinolones (especially moxifloxacin). Patients on these drugs should have regular electrocardiograms (baseline, at two weeks, and then at least monthly) to monitor for QTc prolongation; more frequent monitoring is warranted for patients on multiple QTc-prolonging drugs or in the setting of risk factors. In addition, such patients should have electrolytes checked regularly (baseline, at two weeks, and then at least monthly). (See 'Bedaquiline' above.)

Neurotoxicity — Forms of neurotoxicity associated with antituberculous drugs include peripheral neuropathy and central nervous system toxicity (including psychiatric effects, seizures, and serotonin syndrome).

Perioral numbness (transient, nonprogressive) has been reported in patients receiving streptomycin; it may be managed with dose and/or interval reduction accompanied by serum drug concentration monitoring to assure target concentrations are achieved.

Peripheral neuropathy — Antituberculous drugs most commonly associated with peripheral neuropathy include isoniazid, ethionamide, cycloserine, and linezolid. Fluoroquinolones and ethambutol have rarely been associated with peripheral neuropathy.

The likelihood of neuropathy is increased in patients with diabetes, alcoholism, HIV infection, hypothyroidism, pregnancy, and poor nutrition (with inadequate dietary intake of pyridoxine).

If dietary intake of vitamin B6 is insufficient (less than 0.5 to 2 mg daily for children and adults), pyridoxine should be administered to patients on regimens including isoniazid, ethionamide, cycloserine, or linezolid [82]. Patients on a standard regimen for treatment of drug-susceptible TB should receive pyridoxine 50 mg daily. Patients on treatment for multidrug-resistant TB should receive pyridoxine 100 mg daily. Higher doses of pyridoxine have been associated with an increased risk of peripheral neuropathy and are not recommended routinely [24].

Neuropathy associated with linezolid usually occurs after four months of therapy but can occur earlier. In some patients, symptoms may respond if linezolid doses of 600 mg once daily are reduced (to 300 or 450 mg once daily or 600 mg three to four times weekly) with serum concentration monitoring performed to ensure therapeutic concentrations are achieved.

Symptomatic treatment of peripheral neuropathy with neuroleptics (such as gabapentin, pregabalin, carbamazepine, or low-dose tricyclic antidepressants) may facilitate the continuation of therapy in some patients.

Central nervous system toxicity — Forms of central nervous system toxicity associated with antituberculous drugs include psychiatric effects, seizures, and serotonin syndrome.

●Psychiatric effects – Drug-induced depression can occur with cycloserine, ethionamide, and (less frequently) isoniazid or ethambutol. In patients on cycloserine or ethionamide, depression may be severe and accompanied by suicidal ideation requiring drug discontinuation. Patients with depression should have a serum drug concentration obtained, and the dose should be reduced if feasible (table 7).

Patients with suicidal ideation who are on isoniazid and/or ethambutol should have these drugs discontinued. Mild depression may be managed with continuation of therapy and supportive care. Antidepressants may be used, but patients on linezolid may not take selective serotonin reuptake inhibitors or tricyclic antidepressants (due to the risk of serotonin syndrome).

Drug-induced psychosis has been reported with the use of cycloserine, fluoroquinolones, and (less frequently) isoniazid. Patients with psychosis should be treated with pyridoxine (100 mg if not already given) along with antipsychotic therapy. Cycloserine should be discontinued and a serum drug concentration obtained. Some patients may tolerate cycloserine with an antipsychotic drug if no other treatment options are available. Cycloserine may be restarted at a lower dose with titration guided by serum drug concentration monitoring.

●Seizures – Drug-induced seizures can occur with cycloserine, fluoroquinolones, linezolid, isoniazid, and carbapenems. These drugs should be discontinued in patients with seizures. Patients on cycloserine should have a serum drug concentration obtained. (See "Isoniazid (INH) poisoning", section on 'Seizure management'.)

Patients should be treated with anticonvulsant therapy for the duration of the treatment regimen. Once seizures have resolved, medications may be restarted one at a time. Patients with suspected isoniazid-induced seizures who resume isoniazid should take concomitant pyridoxine. Cycloserine should be restarted only if it is absolutely essential.

●Serotonin syndrome – Serotonin syndrome may result from the coadministration of linezolid with a serotonin reuptake inhibitor, a tricyclic antidepressant, or a diet high in tyramine-containing foods (such as cheese, wine, cured meats, soy sauce, and fermented foods). Signs and symptoms include clonus, agitation, tremor, and/or hyperthermia. (See "Serotonin syndrome (serotonin toxicity)".)

Ototoxicity — Aminoglycosides and capreomycin can cause vestibular and auditory toxicity, even if serum drug concentrations are within the therapeutic range. Toxicity is related to the total dose and is cumulative. (See 'Injectable-only agents' above.)

Patients receiving these agents should have monthly assessments for vestibular and auditory toxicity. Symptoms attributed to the injectable agent (such as tinnitus, unsteadiness, or hearing loss) should prompt elimination of the entire drug class and rechallenge should not be attempted.

For patients with fullness in the ears (which may be an early symptom of vestibular toxicity), the dosing interval may be reduced from daily to three times a week (after three to four months of treatment with negative sputum cultures).

Nephrotoxicity — Aminoglycosides and capreomycin can cause nephrotoxicity and electrolyte disturbances. Patients receiving these drugs should have weekly serum creatinine monitoring for the first several weeks, then at least monthly, in addition to monthly electrolyte monitoring (potassium, calcium and magnesium) with repletion as needed. The optimal frequency of serum drug concentration monitoring for injectable agents is uncertain; it is often performed weekly during the initial phase of treatment (while on daily therapy) and any time there are changes in serum creatinine or following dose adjustments.

Drug dose adjustments should be made for patient with renal dysfunction (table 4).

Hematologic effects — Hematologic abnormalities associated with antituberculous drugs (notably isoniazid, rifampin, and linezolid) may involve any cell line (table 9). It may be difficult to differentiate abnormalities due to antituberculous therapy from hematologic effects due to TB or other underlying diseases.

Hematologic abnormalities in patients receiving treatment for TB may reflect comorbid diseases such as renal insufficiency, nutritional deficiency, malignancy, HIV infection, or bone marrow suppression due to other drugs. They may also occur as a result of bone marrow involvement associated with TB.

If other causes are excluded, TB drugs associated with hematologic abnormalities should be discontinued until counts have recovered; thereafter, the drugs should restarted one at a time with close hematologic monitoring. Drug(s) associated with recurrent hematologic abnormalities should not be continued.

When hematologic toxicity due to linezolid is mild and resolves off therapy, linezolid may be resumed at a lower dose (eg, 300 mg instead of 600 mg). In such settings, monitoring of serum concentrations is necessary to assure adequate therapeutic concentrations.

Ophthalmic toxicity — Antituberculous drugs associated with optic nerve toxicity include ethambutol, linezolid, ethionamide, and isoniazid. Clofazimine toxicity produces a pigmentary maculopathy and generalized retinal degeneration. Ophthalmic toxicity associated with these agents should prompt ophthalmology referral and drug discontinuation. Rifabutin can cause a pan-uveitis that is reversible with holding therapy and resumption with dose adjustment.

Patients taking ethambutol should be monitored monthly for ophthalmic symptoms, which can be dose and duration related. Monthly visual acuity and color discrimination evaluation is warranted for patients receiving ethambutol (≥25 mg/kg) and/or patients receiving the drug for longer than two months.

Musculoskeletal effects — Myalgias and arthralgias are common in patients taking antituberculous therapy and may be associated with pyrazinamide, fluoroquinolones, rifabutin, isoniazid, ethionamide, and bedaquiline. These manifestations do not warrant drug discontinuation and may reflect drug-induced electrolyte disturbances or thyroid dysfunction.

Tendonitis and tendon rupture have been associated with fluoroquinolone use. The drug may be continued in the setting of mild tendon inflammation but should be discontinued in the setting of significant inflammation.

Endocrine effects — Endocrine effects associated with antituberculous drugs include hypothyroidism, gynecomastia, and dysglycemia.

Hypothyroidism may develop with para-aminosalicylic acid or ethionamide; when used in combination, the incidence of hypothyroidism may be ≥40 percent [5]. Patients on these drugs should have baseline and monthly thyroid function assessment. When thyroid stimulating hormone rises to >1.5 times the upper limit of normal, thyroid hormone replacement should be initiated. (See "Treatment of primary hypothyroidism in adults".)

Gynecomastia can occur in patients on ethionamide; the drug may be continued and gynecomastia resolves when treatment is stopped.

Hypoglycemia has been associated with linezolid. Fluoroquinolones, particularly gatifloxacin (no longer available in the United States for this reason), can cause hypoglycemia or hyperglycemia.

Other adverse effects — Miscellaneous adverse effects are summarized below.

●Metallic taste – Metallic taste can occur in patients on ethionamide or fluoroquinolones. Patients should be encouraged to tolerate this side effect, which resolves when treatment is stopped.

●Flu-like syndrome – Flu-like syndrome has been reported with isoniazid, rifampin, and rifapentine. The rifamycins can cause a flu-like syndrome beginning one to two hours after administration and resolving six to eight hours later. Typically, this syndrome occurs more commonly with intermittent rather than daily therapy, particularly at higher doses. This is discussed separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Adverse effects'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY

●First-line agents – First-line agents for treatment of tuberculosis (TB) consist of isoniazid, rifampin (or rifapentine or rifabutin in certain situations), pyrazinamide, ethambutol, and moxifloxacin. Dosing for first-line agents is summarized in the table (table 1 and table 2). (See 'First-line agents' above.)

●Second-line agents – Presence of drug resistance or intolerance to first-line agents warrants use of second-line agents. These agents are so classified because of relative lack of clinical data, unfavorable or poorly characterized pharmacokinetic profile, and/or increased incidence and severity of adverse events. Categories of second-line agents are summarized in the table (table 3). Antituberculous agents should be used in combination for treatment of TB disease, guided by in vitro susceptibility results and selected with involvement of an expert in the treatment of TB. Dosing for second-line agents is summarized in the table (table 4). (See 'Second-line agents' above.)

●Fluoroquinolones – In general, levofloxacin and moxifloxacin are favored over the early-generation fluoroquinolones for treatment of TB. There is no role for use of more than one fluoroquinolone in a treatment regimen since all drugs in the class share a genetic target. Cross-resistance between fluoroquinolones is common but not universal. (See 'Fluoroquinolones: levofloxacin or moxifloxacin' above.)

●Clinical and laboratory monitoring – Patients receiving antituberculous therapy should undergo baseline measurement of liver function tests (serum bilirubin, alkaline phosphatase, and transaminases). Serial liver function measurements are not necessary for patients with normal baseline results and no risk for hepatitis; monthly liver function tests should be obtained in the clinical settings outlined above. (See 'Clinical and laboratory monitoring' above.)

●Therapeutic drug monitoring – Indications for therapeutic drug monitoring include (but are not limited to) use of injectable-only agents or cycloserine, presence of renal impairment, and regimens with potentially significant drug-drug interactions (table 7). (See 'Serum drug concentration monitoring' above.)

●Gastrointestinal effects – Gastrointestinal symptoms may be associated with a number of antituberculous agents, including ethionamide, para-aminosalicylic acid (the latter two particularly in combination), linezolid, levofloxacin, moxifloxacin, clofazimine, and bedaquiline. Strategies include symptomatic management; it may be possible to make drug dose adjustments in some cases. (See 'Gastrointestinal effects' above.)

●Hepatotoxicity – Management of hepatotoxicity should be guided by liver function test results (algorithm 1 and algorithm 2). In general, all hepatotoxic drugs should be discontinued if the serum bilirubin is ≥3 mg/dL (≥51 mcmol/L) or serum transaminases are more than five times the upper limit of normal. Thereafter, once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring between resumption of each agent. (See 'Hepatotoxicity' above.)

●Dermatologic effects – Dermatologic reactions associated with antituberculous drugs include maculopapular rash (any antituberculous drug), flushing (rifampin or pyrazinamide), photosensitivity (pyrazinamide, clofazimine, or fluoroquinolones), lichenoid reactions (ethambutol, isoniazid, streptomycin, and cycloserine), and hives (any antituberculous drug). (See 'Dermatologic effects' above.)

●Severe systemic reactions – Severe systemic reactions associated with antituberculous drugs include anaphylaxis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Antituberculous drugs should be discontinued in the setting of systemic symptoms, fever, urticaria, mucous membrane involvement, blistering, edema of the lips or eyes, wheezing, or airway compromise. Referral to an allergist with experience in drug allergy should be considered for more severe reactions. (See 'Severe systemic reactions' above.)

●QT prolongation – Drugs associated with QT interval prolongation include bedaquiline, clofazimine, delamanid, and fluoroquinolones (table 6). Patients on these drugs should have regular electrocardiograms (baseline, at two weeks, and then at least monthly) to monitor for QTc prolongation; more frequent monitoring is warrant for patients on multiple QTc-prolonging drugs or in the setting of risk factors. In addition, such patients should have electrolytes checked regularly (baseline, at two weeks, and then at least monthly). (See 'QT prolongation' above.)

●Neurotoxicity – Forms of neurotoxicity associated with antituberculous drugs include peripheral neuropathy (isoniazid, ethionamide, cycloserine, and linezolid) and central nervous system toxicity (psychiatric effects [depression can occur with cycloserine or ethionamide; psychosis can occur with cycloserine, fluoroquinolones, or isoniazid], seizures [fluoroquinolones, linezolid, isoniazid, and carbapenems], and serotonin syndrome [linezolid]). (See 'Neurotoxicity' above.)

●Ototoxicity and nephrotoxicity – The aminoglycosides and capreomycin can cause vestibular toxicity, auditory toxicity, nephrotoxicity, and electrolyte disturbances. Patients on these agents should have monthly assessments for vestibular and auditory toxicity, close monitoring of renal function and electrolytes, and therapeutic drug monitoring. (See 'Ototoxicity' above and 'Nephrotoxicity' above.)

●Hematologic effects – Hematologic abnormalities associated with antituberculous drugs may involve any cell line. The most common causes of hematologic abnormalities among the antituberculous drugs include isoniazid, rifampin, and linezolid; these are summarized in the table (table 9). (See 'Hematologic effects' above.)

●Ophthalmic toxicity – Antituberculous drugs associated with optic nerve toxicity include ethambutol, linezolid, ethionamide, and isoniazid. Clofazimine toxicity produces a pigmentary maculopathy and generalized retinal degeneration. Rifabutin can cause a pan-uveitis that is reversible with dose adjustment. (See 'Ophthalmic toxicity' above.)

●Other adverse effects – Other adverse effects associated with antituberculous drugs include musculoskeletal effects, endocrine effects, and other effects. (See 'Musculoskeletal effects' above and 'Endocrine effects' above and 'Other adverse effects' above.)